C O N S E N S U S S T A T E M E N T

Detection and Management ofLipid Disorders in Diabetes

A ltered concentrations of blood plasmalipoproteins are powerful predictorsof coronary heart disease (CHD) and

of other manifestations of atherosclerosis.Reduction of elevated low-density lipopro-tein cholesterol (LDL cholesterol) and con-comitant increases in high-density lipopro-tein cholesterol (HDL cholesterol) have beenshown to reduce myocardial infarction anddeath from CHD in people with no previoushistory of vascular events. Other studies us-ing angiography have demonstrated that theatherosclerotic lesions can be stabilized orcaused to regress in the coronary vessels ofpatients who have clinically evident disease.

Diabetes mellitus markedly increasesthe risk of death and disability from thevarious complications of atherosclerosis. Sev-enty-five to 80% of adult diabetic patientsdie from CHD, cerebrovascular disease,and/or peripheral vascular disease. The lipo-protein risk factors defined in the generalpopulation also occur in diabetic patients.Elevated LDL cholesterol, reduced HDLcholesterol, and hypertriglyceridemia are fre-quently found in insulin-dependent diabetesmellitus (IDDM) and non-insulin-depen-dent diabetes mellitus (NIDDM). There isconsiderable evidence that higher blood tri-glycerides and lower HDL cholesterol maybe intrinsically related to the abnormal phys-iology produced by insulin resistance orinadequate insulin action, with the concom-itant metabolic disturbances.

The significant advances in theunderstanding of lipoprotein structureand metabolism, as well as the large bodyof data illustrating the efficacy of treatinglipoprotein disorders, stimulated theAmerican Diabetes Association to exam-ine the possibility of better defining andaltering vascular disease risk associated

APPROVED IN JANUARY 1993.

with diabetes mellitus. Studies of diabe-tes in special ethnic groups, physiologi-cal characteristics of glucose/insulin andlipoprotein interrelationships, and theeffect of various interventions using diet,exercise, and drug therapy of lipoproteindisorders are now available for the plan-ning of new clinical strategies in vasculardisease prevention. These developmentsled to the consensus development con-ference on the Detection and Managementof Lipid Disorders in Diabetes held inDallas, Texas, on 11-13 January 1993.Presentations by 24 experts in a varietyof relevant subjects were given over a2-day period. An eight-member panelwith clinical and research experience innutrition, epidemiology, physiology, andthe care of patients with diabetes andlipid disorders considered a broad spec-trum of issues. An audience of healthprofessionals joined the panel in thediscussion of the material presented. Thereport of this panel is provided in theform of answers to the following ques-tions:

1. What is the epidemiology of lipidlevels in diabetes?

2. What is the relationship betweenlipid levels and cardiovascular dis-ease (CVD) in diabetes?

3. Are lipid disorders different inpeople with diabetes, and, if so,what is the pathophysiology ofthis difference?

4. What can be accomplished by thevarious treatments of lipid disor-ders in diabetes?

5. What are the goals of therapy forlipid disorders in diabetes?

6. What further research is neededon this subject?

QUESTION 1: WHAT IS THEEPIDEMIOLOGY OF LIPID LEVELSIN DIABETES?—NIDDM is primarilya disease of middle-aged or older adults.The mean age of incident cases in Cauca-sians is —60 yr; in minority populations,such as African Americans, Hispanics,and Native Americans, the disease ap-pears 10-15 yr earlier. The incidence ofNIDDM increases with age. Most(-80%) NIDDM patients in the U.S. areoverweight, at least during the earlystages of their disease. Early studiesshowed a considerable and strong rela-tionship between a simple measure ofobesity, such as body mass index, and riskof diabetes. Subsequently, it was shownthat body fat distribution, as measured bya high waist-to-hip ratio, was an impor-tant risk factor for the development ofNIDDM. The most recent studies havesuggested that deep abdominal or mesen-teric fat is a more specific risk factor forNIDDM. The increase in mesenteric fatmay be related to a higher fat intake in thediet. Some studies have also suggested thatdecreased physical activity may be a riskfactor for diabetes. There is also a verystrong familial and genetic component tothe etiology of NIDDM.

The most common lipid abnor-malities in NIDDM relate to triglycerideand HDL metabolism. NIDDM subjectshave higher triglyceride levels than thegeneral population. These levels areprobably higher than in individuals withthe same degree of obesity who do nothave diabetes. However, there are fewstudies that have measured both abdom-inal fat and fat intake among diabetic andnondiabetic subjects to measure the spe-cific effect of diabetes on triglyceridelevels independent of obesity and diet.The elevated triglyceride levels are not animmutable part of the pathophysiologyof NIDDM. Weight loss will substantiallydecrease the triglyceride levels amongdiabetic and nondiabetic patients. Therealso appear to be relatively little data

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Consensus Statement

comparing triglyceride levels among di-abetic patients in different ethnic groupsand populations.

The levels of HDL cholesterol arelower among NIDDM patients than in non-diabetic subjects. The level of the HDL2

cholesterol subtraction is especially lower inNIDDM patients. The lower HDL cholesterollevels are related to the higher triglyceridelevels, degree of central or intra- abdominalobesity, and glucose and insulin levels. Theepidemiology of HDL cholesterol among di-abetic patients appears to be similar to that innondiabetic subjects. Women with NIDDMtend to have higher HDL cholesterol levelsand higher subtractions of HDL2 cholesterolthan men. The limited data suggest thatAfrican Americans with NIDDM have higherHDL cholesterol levels than Caucasians.

An association among glucose andinsulin levels, obesity, high triglyceridelevels, and lower HDL cholesterol levelshas been found in practically all diabeticpopulations in the U.S. including Cauca-sians, Hispanics, African Americans, Na-tive Americans, Asians, and Indians.

The total cholesterol and LDL cho-lesterol levels are similar among NIDDMpatients and age- and obesity-matchednondiabetic subjects. However, there ap-pears to be a higher prevalence of smalldense LDL particles among NIDDM pa-tients. The small dense LDL particles are,in part, determined by the higher triglyc-eride levels among diabetic patients andmay also have a familial genetic compo-nent. Decreases in triglyceride levelsthrough weight loss lead to a reduction inthe prevalence of dense LDL particles.

LDL cholesterol levels increase withage, at least up to about age 50-55 yr inmen and 65 yr among women. The LDLcholesterol levels will also be higher in pop-ulations that consume more saturated fat andcholesterol in their diet. NIDDM populationsin the U.S. have higher LDL cholesterollevels than similar diabetic populations inJapan. The higher LDL cholesterol levels arethe likely reason for substantial worldwidegeographic variation in risk of CHD amongNIDDM patients. Higher triglyceride levelsare also found in NIDDM patients with the

apolipoprotein (apo) E-II phenotype andelevated LDL cholesterol levels among thosewith the ApoE-IV phenotype.

In the U.S., the Pima Indians, andperhaps other Native American popula-tions, have lower LDL cholesterol levelsthan U.S. Caucasian populations, despiteapparent central obesity, a relativelyhigh-fat diet, and a very high prevalenceof NIDDM. This may account for theirlow prevalence of CHD.

The abnormal lipoprotein levelscharacteristic of NIDDM have also been ob-served among "prediabetic" individuals, es-pecially lower HDL cholesterol and highertriglyceride levels. In most populations, cen-tral obesity and higher insulin levels aredirectly related to triglyceride levels and tolower HDL cholesterol, especially HDL2

cholesterol. Increased blood glucose val-ues, even within the "nondiabetic range"(fasting and after a glucose load), are alsorelated to higher triglyceride and lowerHDL cholesterol levels.

There does not appear to be asubstantial difference in lipoprotein(a)[Lp(a)] levels between NIDDM patientsand control subjects. The data, however,are sparse. There are few data describingdifferences in the distribution of types offatty acids in triglycerides, phospholipid,or cholesterol esters in diabetic individ-uals compared with control subjects.

There is little overall difference inlipoprotein levels in IDDM subjects ingood glycemic control compared withnormal control subjects. Poor control ofIDDM may be associated with high tri-glyceride and LDL cholesterol levels.

QUESTION 2 : WHAT IS THERELATIONSHIP BETWEEN LIPIDLEVELS AND CVD INDIABETES? —The risk of CVD amongdiabetic patients is directly related to thelevels of blood pressure, cigarette smok-ing, and total cholesterol. The combina-tion of these risk factors substantiallyincreases the rate of CVD. At any level ofthese risk factors, diabetic patients prob-ably have four to five times the risk of

CVD compared with nondiabetic indi-viduals.

There is a paucity of evidenceshowing an increased risk of cardiovas-cular complications in relation to theHDL cholesterol or triglyceride levelsamong diabetic subjects. However, thelimited data that are available would sug-gest that low HDL cholesterol levels andprobably high triglyceride levels are inde-pendent risk factors for cardiovascular dis-ease among NIDDM patients. There is alsoan inconsistent relationship between bloodglucose and/or insulin levels, and the riskof CHD or CVD among NIDDM patients.

In diabetic populations that con-sume a diet low in saturated fat and choles-terol and have a low LDL cholesterol, theincidence of and mortality due to CHD isrelatively low. Most diabetic patients areobese. Abdominal obesity appears to be anindependent CHD risk factor and is di-rectly related to insulin and triglyceridelevels and inversely related to HDL choles-terol levels. It has not been conclusivelydetermined whether any of the followingparameters are independent determinantsof the risk of CVD among diabetic sub-jects: lower HDL cholesterol or highertriglyceride levels, insulin resistance, ele-vated glucose levels, abnormal composi-tion of lipoproteins, the effects of lipopro-teins on clotting or fibrolysis, or urinaryalbumin excretion rates.

Metabolic studies have proposed in-sulin resistance as a possible mechanismaccounting for the excess cardiovascular riskHowever, there are neither long-term obser-vational studies nor intervention trials tosubstantiate this important hypothesis. Also,to date, there is little evidence that Lp(a)levels are associated with increased risk ofCVD among diabetic patients.

QUESTION 3 : ARE LIPIDDISORDERS DIFFERENT INPEOPLE WITH DIABETES AND,IF S O , WHAT IS THEPATHOPHYSIOLOGY OF THISDIFFERENCE? —The pathophysiologyof lipid metabolism in diabetes mellitusdepends on the nature of the underlying

DIABETES CARE, VOLUME 16, SUPPLEMENT 2, MAY 1993 107

Consensus Statement

metabolic defect. Disturbances in lipidmetabolism may induce alterations in thevarious lipids and lipoproteins in theplasma, due to either changes in syn-thetic or fractional clearance rates, alter-ations in the composition of the lipopro-tein particles, or differences in thedistribution of subspecies of particles.The specific lipid pattern observed willbe influenced by genetic factors, as mod-ified by environmental influences on themetabolic milieu of the individual.

Numerous observations in IDDMsubjects indicate that patients who aremaintained near normoglycemia havenormal levels of very-low-density lipo-protein (VLDL) triglyceride and choles-terol and LDL-C but slightly elevatedlevels of HDL cholesterol. When insulindeficiency occurs, hyperglycemia is ac-companied by extremely elevated VLDLtriglyceride and sometimes small in-creases in LDL cholesterol can be ob-served (particularly noted in adolescentwomen). Hyperglycemic IDDM patientshave a qualitative change in LDL parti-cles. The small dense LDL (Sf 3-6) andintermediate-density lipoprotein parti-cles are increased, whereas more bouyantLDL particles (Sf 6—12) are decreased.Because lipoprotein lipase is insulin de-pendent, adipose tissue enzyme activityis reduced. Lp(a) levels may be increasedonly in a subset of IDDM patients whohave microalbuminuria. Cholesterol es-ter transport is increased presumablybecause the VLDL particle is abnormaland not because cholesterol ester trans-port protein activity is altered. Intensiveinsulin treatment of IDDM patients willnormalize most of the VLDL and LDLabnormalities and enzyme activities ifnear normoglycemia is maintained for3—6 mo. However, composition of VLDLand HDL particles in IDDM patientsshow abnormal free cholesterol enrich-ment, which is quite resistant to correc-tion by even normoglycemic regulation.

Other factors can adversely influ-ence lipid and lipoprotein metabolism indiabetic patients. These include I) anincrease in urinary albumin excretion

rate, 2) development of uremia, 3) typeof diet, 4) certain antihypertensive drugs,5) hypothyroidism, and 6 underlyinggenetic lipid disturbances.

Lipid and lipoprotein abnormali-ties appear to be an integral part of theinsulin-resistance syndrome with orwithout NIDDM. Individuals with thesyndrome of increased intra-abdominalobesity have increased levels of VLDLparticles and total triglycerides and de-creased HDL cholesterol levels whencompared with normal control subjectsor individuals with lower body obesity.Individuals with increased intra-abdom-inal obesity show marked peripheral andhepatic resistance to insulin action. Insu-lin secretion is increased and hepaticinsulin extraction is decreased leading toincreased insulin levels. The increasedVLDL particles are due to an increasedsecretory rate from the liver. An in-creased free fatty acid flux, and perhapsincreased glucose, play a significant rolein the increased triglyceride synthesis.Lipoprotein lipase and hepatic triglycer-ide lipase activities may also be dimin-ished. The decreased HDL cholesterol iscaused by an increased transfer of cho-lesterol ester to triglyceride-rich lipopro-teins and an increase in HDL clearance.An increase in small dense LDL particlesis also present. The major factors causingthese metabolic changes are insulin resis-tance and the degree of abdominal obe-sity. NIDDM occurs in these patientswith abdominal obesity when the P-cellscannot maintain compensatory hyperin-sulinemia. As the insulin levels decrease,VLDL fractional clearance may furtherdecrease, LDL receptor activity de-creases, and hepatic glucose productionrises. More severe hyperglycemia is asso-ciated with greater abnormalities inVLDL triglyceride and HDL cholesterollevels. The VLDL overproduction reflectsincreases in ApoB and triglyceride syn-thesis but the relative increments in tri-glyceride and ApoB content of the parti-cles may vary.

The composition of lipoproteinparticles in NIDDM is also altered. VLDL

particles contain relatively greater num-bers of larger particles (Sf > 60) that areenriched in other lipids and may havelower triglyceride content. The smallerVLDL particles (Sf 20-60) are enrichedin cholesterol and non-ApoB proteins.The HDL cholesterol compartmentshows a reduction in HDL subspeciesand a reduced ApoA: cholesterol ratio.LDL cholesterol particles have an in-crease in triglycerides. Several observa-tions show that patients with diabetesdevelop more atherogenic disease thannondiabetic subjects with the samequantitative lipid and lipoprotein pro-files, suggesting that LDL particles inpeople with diabetes may differ fromthose in normal subjects.

Studies in normal subjects andNIDDM individuals indicate that LDLparticles are found in two major distri-bution patterns. The A pattern consists ofa major peak of LDL: or LDL2 particles(Sf 6—12 class). The B pattern consists ofa major peak of LDL3, which is thesmaller, more dense particle (Sf 3-6class). The B pattern is associated withhigher levels of triglycerides, LDL cho-lesterol and ApoB, and lower levels ofHDL cholesterol and ApoA, than the Apattern. The frequency of the B pattern isincreased in NIDDM and insulin-resistant states.

Both clinical and laboratory in-vestigations show that lipoprotein parti-cles are modified in NIDDM by glyca-tion, the formation of advancedglycosylation products, aggregation, andoxidation. All of these processes occurwith greater frequency in patients withhyperglycemia. Glycated LDL particlesare cleared through an LDL-receptor-independent mechanism. The clearanceof these particles with altered constitu-ents is prolonged by 10-25% comparedwith normal particles. Oxidized and gly-cated LDL particles have an increaseduptake by macrophages and are thoughtto increase the production of foam cellsand stimulate the atherogenic process.Some studies indicate that glycation andoxidation may facilitate each other.

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QUESTION 4: WHAT CAN BEACCOMPLISHED BY THEVARIOUS TREATMENTS OF LIPIDDISORDERS IN DIABETES?

Diet and exerciseNutrition and physical activity changesare cornerstones in the management oflipid disorders in people with diabetes.The goals of dietary therapy should be toaffect the underlying metabolic distur-bances related to lipid disorders. Treat-ment of lipid disorders in diabetic sub-jects should focus on three majorstrategies: an aggressive approach toweight loss as indicated, increased phys-ical activity, and a low-fat (<30% Kcalfat) low-saturated fat dietary pattern.

Weight reduction in overweightpatients should be recommended for in-dividuals considered "prediabetic" and forthose with diagnosed diabetes. Weight lossis associated with improvements in triglyc-erides, insulin sensitivity, glucose control,and reduction in total cholesterol and LDLcholesterol, and increases in HDL choles-terol levels. Generally, the greater theweight loss, the greater the improvementin these parameters, but even with aweight loss of <10 lb, improvement inlipid patterns has been observed. Weightloss should be achieved by reducing totalcalorie intake and total fat intake and byincreasing physical activity.

Physical activity should be rec-ommended as part of the management oflipid disorders in diabetic subjects. In-creased caloric expenditure throughphysical activity should be used as partof weight-loss treatment. This increasedphysical activity has been shown to en-hance total weight loss and to facilitateweight maintenance. The resultingchanges in body weight and body com-position lower triglyceride, total choles-terol, and LDL cholesterol levels, andincrease HDL cholesterol levels.

Recommendations for increasedphysical activity should be individual-ized, with the recognition that manydiabetic patients have low levels of fit-ness. Undertaking a program of increased

exercise will be difficult and require moti-vation, support, and follow-up. Gradualincreases in low-intensity physical activityshould be recommended and can provideimportant benefits.

Recommendations for increasedphysical activity need to be made in thecontext of the patient's history and medicalstatus. Medical evaluation for diabeticcomplications and cardiovascular diseaseare needed before a patient begins anexercise program. Physical activity mayincrease risks associated with severe car-diovascular and microvascular disease.

The dietary pattern recom-mended for the treatment of lipid disor-ders in diabetes includes:

Calorie restriction for individualsneeding weight loss.

Total fat intake <30% of Kcal.Saturated fat intake <10% of total

Kcal. Reduction to <7% of totalKcal may also provide greater re-duction in total cholesterol and LDLcholesterol.

Total cholesterol intake of <300 mg/day; further reduction to <200 mg/day may also provide greater reduc-tion in total cholesterol and LDLcholesterol levels.

Carbohydrate intake of 50-60% of totalcalories. The diet pattern should em-phasize complex carbohydrates andinclude at least 5 portions/day offruits and vegetables. Sources of sol-uble fiber (legumes, oats, and somefruits and vegetables) may have ad-ditional beneficial effects on totalcholesterol and LDL cholesterol lev-els as well as on the glycemic index.The choice of appropriate carbohy-drate sources to maintain glycemiccontrol is a critical component ofdietary treatment.

The American Diabetes Associa-tion exchange diet provides the founda-tion for dietary changes for both weightloss and fat reduction. This diet pro-vides the framework for choosingfoods, based on carbohydrate and fatcontent, with the specific intent of gly-

cemic control. It provides patients withthe structure needed for meal planning,portion control, and dietary self-moni-toring; techniques that have beenshown to improve weight loss and di-etary fat reduction in many settings.Additional education should be pro-vided on the saturated fat and choles-terol content of foods. Optimal dietarytherapy should include referral to a reg-istered dietitian for individualization ofthe diet treatment plan and appropriatenutrition education.

For diabetic patients who havehypertension, in addition to lipid ab-normalities, the dietary treatment ap-proach would be the same as describedabove with the addition of sodium re-duction to <2400 mg/day. Weight lossof >10 lb can have a significant effecton lowering blood pressure. As withlipids, the greater the weight loss, thegreater the blood pressure lowering.

Glucose controlLipid abnormalities often characterizepoorly controlled diabetic patients. Hy-pertriglyceridemia, hypercholesterol-emia, and low HDL cholesterol levelsmay greatly improve with aggressivetreatment of hyperglycemia. Therefore,the first approach to hyperlipidemia in thediabetic patient should be optimization ofdiabetes control with diet, exercise, and,when indicated, oral antihyperglycemicagents and/or insulin.

In IDDM, the occurrence of dia-betic ketoacidosis results in a profounddisorder of lipid metabolism. Severe hy-pertriglyceridemia, elevated nonesteri-fied fatty acids, and low lipoprotein li-pase activity in association with reducedLDL cholesterol and HDL cholesterollevels are improved within hours of ad-equate insulin therapy. The beneficialeffects on lipids of correcting less severemetabolic derangements in IDDM areless dramatic but still important. Therecent results of the Diabetes Controland Complications Trial have demon-strated that intensified insulin therapycan achieve greatly improved average

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Consensus Statement

glycemic levels in motivated IDDM pa-tients. Intensified insulin therapy in-volves the combination of education, dietplanning, scheduled exercise, and multi-ple insulin injections in combinationwith self-monitoring of blood glucose.Whether this approach or a less-intensive treatment regimen is used isnot crucial as long as the goal of therapyis to bring the average blood glucosevalue as close as possible to the upperlimit of normal, usually assessed by theglycosylated hemoglobin concentration.

The normal-weight patient withIDDM who has acceptable blood glucosecontrol is usually characterized by lipidlevels in the normal range. However, thecomposition of lipoprotein particles maybe abnormal. These abnormalities may berelated to the abnormal daily glucose pat-tern achieved with existing therapies, thehyperinsulinemia that accompanies subcu-taneous administration of insulin, or othermetabolic/genetic abnormalities that coex-ist with the diabetic state. Correction ofthese abnormalities is not yet possible.

In NIDDM patients, hypertriglyc-eridemia, a tendency for reduced HDLcholesterol levels, and an abnormal com-position of lipoproteins are characteris-tic. Although treatment of the hypergly-cemia in these patients is necessary, itusually does not completely correct thelipid abnormalities to normal. Treatmentof the insulin resistance in NIDDM isbest approached with emphasis on diet-induced weight loss and a physical exer-cise program. Because the insulin resis-tance may be the underlying cause of thehyperlipidemia in NIDDM, a major effortby the patient and health-care teamshould be devoted to improving the pa-tient's life-style. Unfortunately, pharma-cological interventions aimed at increas-ing insulin sensitivity in NIDDM are notavailable for clinical use.

Pharmacological therapyIf there is an unacceptable response to anadequate therapeutic trial of diet, exer-cise, and improved glucose control, lip-id-lowering pharmacological agents are

the next therapeutic tool. Currently, therehave been no primary or secondary preven-tion trials of lipid-lowering agents in diabeticpatients. To the contrary, most trials havesystematically excluded diabetic subjects.Thus, a complete characterization of phar-macological agents with respect to theireffects in diabetes is necessarily limited tothe existing literature, which consists pri-marily of short-term studies in relativelysmall populations. The following classes oflipid-lowering agents may be used, as in-dicated, for the treatment of one or more ofthe lipid disorders seen in diabetes.

Bile acid binding resinsThese agents (colestipol and choles-tyramine) are insoluble ion-exchange res-ins that selectively, but not exclusively,bind bile acids and sequester them withinthe gastrointestinal tract, thereby prevent-ing their enterohepatic recirculation. As aconsequence, hepatic sterol biosynthesis isaccelerated toward bile aicd productionand cell surface LDL receptors (Apo-B/Ereceptors) are increased in number. Becauseof these actions, bile acid binding resinslower primarily total and LDL cholesteroland have little effect on HDL cholesterol.Bile acid binding resins have been effectivein reducing CHD in both primary andsecondary prevention trials, whether usedalone or in combination with other agents.

These agents can elevate VLDLtriglyceride levels, particularly if they arealready elevated above 250 mg/dl. Thus,bile acid resins may be problematic asprimary therapy in patients with NIDDMbecause mild to moderate triglycerideelevation is the most frequent lipid ab-normality. Also, isolated hypercholester-olemia is relatively uncommon in eitherIDDM or NIDDM, and accounts for<10% of all dyslipidemias. However,mixed or so-called "combined" dyslipi-demias in diabetes, consisting of bothcholesterol and triglyceride elevations,are much more common in, and muchless amenable to, mono therapy in dia-betic patients. Thus, small dosages of bileacid binding resins may be used as adju-vant therapy for patients with both VLDL

and LDL elevations, particularly if afibric acid derivative is used as primarytherapy. Similarily, for patients with fa-milial hypercholesterolemia, combina-tion reductase inhibitor—bile acid bind-ing resin therapy—is generally moreefficacious and less toxic than monother-apy with reductase inhibitors alone.

Bile acid binding resins should beused with great care in the elderly or indiabetic patients with gastrointestinal auto-nomic neuropathy because these resins mayproduce constipation or even fecal impac-tion. These agents do not have an adverseeffect on glucose control.

Fibric acid derivativesGemfibrozil and clofibrate are the onlyfibric acid derivatives available in theU.S. These drugs activate lipoprotein li-pase, reduce VLDL triglyceride, increaseHDL cholesterol, and have some variablebut generally small time-dependent ef-fects on LDL cholesterol levels. One ofthese agents, gemfibrozil, has been usedeffectively in a CHD primary preventiontrial (Helsinki Heart Study) in whichnondiabetic and diabetic patients wereenrolled. The direction and magnitude ofchange in lipid levels in the diabeticpatients paralleled the changes seen inthe nondiabetic population.

The greatest benefit in CHD re-duction in the Helsinki Trial was notedin patients with mixed dyslipidemias,including high triglyceride, high LDLcholesterol, and low HDL cholesterollevels. In these patients, coronary eventswere reduced —70%.

Fibric acid derivatives do not appearto alter carbohydrate tolerance in diabeticpatients. However, the fibrates as a class mayincrease the incidence of cholelithiasis, acondition already more prevalent in diabeticpopulations. In patients with extremely hightriglyceride levels, treatment with gemfi-brozil may cause an elevation of LDL cho-lesterol levels as triglyceride levels fall. Per-sistent diet and continuing pharamacologicaltherapy appear to overcome this effect. Un-like bile acid binding resins and HMG-CoAreductase inhibitors, which require 4-8 wk

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Consensus Statement

for full efficiency, fibrates require a mini-mum of 3 mo and probably 6 mo to achievea full effect.

For diabetic patients with mixeddyslipidemias having persistent LDL choles-terol elevations after an adequate trial ofgemfibrozil, small dosages of bile acid bind-ing resins may produce satisfactory reduc-tions of LDL cholesterol.

HMG-CoA reductase inhibitorsThese agents specifically inhibit the keyregulatory enzyme for cholesterol bio-synthesis: HMG-CoA reductase, whichproduces mevalonic acid, the first com-pound committed to sterol biosynthesis.As a consequence, hepatic cholesterolsynthesis declines and surface LDL par-ticle receptors (Apo-B/E receptors) areinduced approximately twofold. LDLcholesterol clearance is therefore in-creased, and LDL levels decline 20-35%after 4 -8 wk of therapy with theseagents. Reductase inhibitors have no ef-fect on glucose control, although effectson insulin resistance have not been in-vestigated. These agents should be usedto reduce LDL cholesterol levels in dia-betic patients. In the treatment of familialforms of hypercholesterolemia they canbe used as monotherapy or in combina-tion with bile acid binding resins.Beneficial effects on triglyceride and HDLcholesterol levels have been reported.However, these effects are only marginal inthe low HDL-high triglyceride patient.

Nicotinic acidNiacin and its derivatives have long beenused as lipid-lowering agents in bothdiabetic and nondiabetic patients. Theseagents increase fatty acid reesterificationto triglycerides, lower free fatty acid lev-els, reduce VLDL secretion, and increaseHDL cholesterol levels while decreasingLDL cholesterol levels. Nicotinic acid hasbeen used successfully in primary andsecondary prevention trials, both aloneor in combination with other lipid-lowering agents, and has, in a singlestudy, appeared to improve mortality innondiabetic hyperlipidemic subjects. Ni-

acin also increases insulin resistance, andincreases both fasting and postprandialhyperglycemia and hyperinsulinemia.Although highly regarded as a therapeu-tic agent for patients with mixed dyslip-idemias, the use of nicotinic acid in anyform as first-line therapy in dyslipidemicdiabetic patients is not recommended.These agents should be reserved for pa-tients with refractory dyslipidemias andonly after careful consideration and withconsiderable follow-up evaluation. An in-ability to maintain acceptable control of hy-perglycemia mandates a discontinuation ofthese agents. Nicotinic acid is also relativelycontraindicated in insulin-resistant "predia-betic" patients, because it may accelerate theappearance of clinical diabetes. In one recentstudy 6% of established nondiabetic patientsconverted to clinical diabetes during 2.5 yr ofniacin therapy (1).

Antioxidant therapiesA number of agents (probucol, vitamins Eand C, and |3-carotene) possess antioxidantproperties that may prevent LDL oxidationand its subsequent uptake by macrophages,thereby potentially slowing atherogenesis.Probucol also reduces total and LDL choles-terol levels by unknown mechanisms. How-ever, this agent also reduces HDL cholesterollevels to an even greater extent. Vitamins Eand C and (3-carotene are each theoreticallyactive as antioxidants with differing loci ofaction; e.g., vitamin E being lipid soluble,whereas vitamin C is water soluble. Thereare several primary and secondary preven-tion trials in progress evaluating these agents.Thus, no firm recommendation for their usecan be made in diabetic patients.

EstrogenPremenopausal women have a much re-duced risk of CHD when compared withmen of the same age. Diabetes mellituslargely, if not completely, obliterates thiscardioprotective effect. Postmenopausalwomen have a gradual increase in coro-nary risk, and postmenopausal womenwith NIDDM are at increased risk forCHD. Recent recommendations from theU.S. Public Health Service on cardiovas-

cular risk include estrogen replacementtherapy in postmenopausal women toreduce CHD risk. Estrogen administra-tion to postmenopausal women raisesHDL cholesteral levels and reduces car-diovascular risk. In diabetic patients withan increased risk for endome trial cancer,unopposed estrogen should not be used.A progestational agent should be in-cluded in hormonal replacement ther-apy. In marked hypertriglyceridemia, es-trogen should be used in minimal doseand with careful followup evaluation.

QUESTION 5: WHAT ARE THEGOALS OF THERAPY FOR LIPIDDISORDERS IN DIABETES? — T h eabsence of intervention trials demonstratingthat correcting lipid abnormalities in patientswith diabetes will reduce the increased riskfor CHD and other macrovascular disordersgreatly complicates the task for recommend-ing goals for therapy. However, the followinginformation can be used in formulating anapproach to treating diabetic patients withlipid disorders:

1. Diabetes is a major risk factor formorbidity and mortality due to CHD,cerebrovascular disease, and periph-eral vascular disease. There is a two-to fourfold increase in the prevalenceof these macrovascular diseases in di-abetic populations.

2. A significant number of patientswith diabetes have lipid disorders.For example, the Early TreatmentDiabetes Retinopathy Study foundthat 36% of subjects had choles-terol levels >240 mg/dl and 26%had LDL cholesterol values >160mg/dl (2).

3. Available data from the Framing-ham Study and the Multiple RiskFactor Intervention Trial suggestthat lipid abnormalities adverselyimpact the development of mac-rovascular disease.

4. Primary and secondary interven-tion trials in nondiabetic subjectshave demonstrated that diet, exercise,and pharmacological therapy de-signed to correct lipid abnormalitiescan decrease progression and even

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Table 1—Lipid levels for adults

RISK FOR ADULT

DIABETIC PATIENTS

ACCEPTABLE

BORDERLINE

HIGH

CHOLESTEROL

(MG/DL)

<200200-239

>240

H D L CHOLESTEROL

(MG/DL)

<35

L D L CHOLESTEROL

(MG/DL)

<130130-159

>160

TRIGLYCERIDES

(MG/DL)

<200200-399

>400

increase regression of angiographi-cally proven CHD. These interven-tions can also decrease the incidenceof CHD events.

5. Intervention trials have included fewsubjects with known diabetes, andno trials were devoted to a popula-tion predominantly composed of pa-tients with either IDDM or NIDDM.However, there are no studies thatsuggest that subjects with diabeteswill not benefit from correction oflipid disorders.

6. Given the increased prevalence ofmacrovascular disease in patientswith diabetes, it is reasonable tosuggest that such patients mighthave a greater benefit from riskfactor amelioration.

Laboratory evaluation for lipiddisorders in diabetesAdult patients with diabetes should be testedfor lipid disorders annually with a fastingserum cholesterol, triglyceride, HDL choles-terol and calculated LDL cholesterol. If allvalues are within acceptable limits, the clini-cian may consider obtaining this lipid profileless frequently. If the cholesterol and LDLcholesterol values are elevated, a serum TSHshould be measured to rule out hypothy-roidism, a not uncommon disorder in pa-tients with diabetes. Pediatric patients withdiabetes should be tested soon after diagno-sis and, if any values are abnormal, annualtesting should be performed. Acceptable,borderline, and high-risk lipid levels foradults are shown in Table 1.

Adult patients without evidence ofmacrovascular disease in the borderline orhigh-risk category, should be treated vig-orously with diet, exercise, and glucosecontrol. If high-risk LDL cholesterol(>160 mg/dl) or triglyceride (>400 mg/dl) values persist after 6 mo of the above

control measures, pharmacological ther-apy should be considered with the goal ofachieving acceptable LDL cholesterol andtriglyceride levels. In addition, adult pa-tients with diabetes and any one of thefollowing major cardiovascular risk factorsshould be considered for pharmacologicaltherapy if they do not achieve acceptableLDL cholesterol and triglyceride levels: anHDL cholesterol <35 mg/dl, cigarettesmoking, hypertension, or a family historyof premature CHD.

Treatment recommendations forlipid disorders in adult diabetic patients mustalso account for the degree of macrovascularrisk. Patients with evidence of macrovasculardisease are at greatest risk for cardiovascularmorbidity and mortality. Based on the resultsof intervention trials in patients without dia-betes, one should strive to achieve the fol-lowing lipid values in these high-risk pa-tients: LDL cholesterol <100 mg/dl andtriglycerides <150 mg/dl.

People with diabetes who havetriglyceride levels >1000 mg/dl are atrisk of pancreatitis and other manifesta-tions of the hyperchylomicronemic syn-drome. These individuals need special,immediate attention.

QUESTION 6 : WHAT FURTHERRESEARCH IS NEEDED ON THISSUBJECTS?—The following studiesare urgently needed to resolve majorissues in the control of lipid levels inpeople with diabetes:

1. Unfortunately, many of the key re-search questions proposed in the1989 American Diabetes Associationconsensus statement on Bole of Car-diovascular Disease in Diabetes haveyet to be answered and should beaddressed with high priority (3).

2. The efficacy of interventions that cansignificantly raise low levels of HDLcholesterol in patients with NIDDMshould be investigated. These studiesshould examine end points involvingthe anatomical and clinical manifesta-tions of atherosclerosis. The specificinterventions should include life-stylechanges that can alter excess body fat(particularly central or intra- abdomi-nal obesity) as well as an assessmentof appropriate lipid-altering drugs.

3. Studies to determine the cardio-vascular benefits of aggressive re-duction of LDL cholesterol in pa-tients with NIDDM below thegoals defined by the NationalCholesterol Education Program.

4. The value of estrogen replacementtherapy in preventing coronary ar-tery disease and/or peripheral vas-cular disease should be tested inpostmenopausal diabetic women.

5. The relationship between intra-ab-dominal fat mass and insulin re-sistance needs to be better denned.Intra-abdominal fat should be quan-titated and related to other aspects ofthe insulin-resistant syndrome atbaseline and after interventions thatreduce the intra-abdominal fat mass.

Acknowledgments—This conference wassupported by an educational grant providedby Parke-Davis, a Division of Wamer-Lam-bert Company.

References1. Brown G, Ackers J, Fisher L, Schaefer S,

Lin J-T, Kaplan C, Zhao X-Q, Bisson B,Fitzpatrick V, Dodge H: Regressing coro-nary artery disease as a result of inten-sive lipid-lowering therapy in men withhigh levels of apolypoprotein B. N Engl JUed 323:1289-98, 1990

2. The Diabetic Retinopathy Study ResearchGroup: Early Treatment Diabetic Reti-nopathy Study design and baseline pa-tient characteristics. Ophthalmology 98(Suppl.):741-56, 1991

3. American Diabetes Association: Role ofcardiovascular risk factors in preventionand treatment of macrovascular disease indiabetes. Diabetes Care 12:573-79, 1989

112 DIABETES CARE, VOLUME 16, SUPPLEMENT 2, MAY 1993